Low-Dose Endoxifen Shows Promise in Reducing Breast Density with Fewer Side Effects Than Tamoxifen

A new study published in the Journal of the National Cancer Institute on April 27 reveals promising results for a breast cancer prevention approach using low doses of (Z)-endoxifen, a metabolite of tamoxifen. The drug reduced mammographic breast density—an established marker of breast cancer risk—with fewer side effects than the standard preventive treatment.

Experts suggest that if further research confirms these findings, (Z)-endoxifen could improve treatment compliance and outcomes. Nearly half of all women aged 40 and older have dense breasts, which is linked to an increased risk of breast cancer.

KARISMA Endoxifen Trial: Study Design and Key Findings

The KARISMA Endoxifen trial, a double-blind, randomized, placebo-controlled phase II study, enrolled 240 premenopausal women aged 40 to 55. Participants were recruited from Sweden’s national breast cancer screening program between December 2021 and November 2023.

Eligible participants had regular menstrual cycles or confirmed premenopausal status via blood tests, along with a baseline mammogram showing measurable breast density. Women taking medications that could interfere with endoxifen metabolism were excluded.

Participants were randomly assigned to one of three groups receiving daily oral capsules for six months:

• A placebo group
• A group receiving 1 milligram (mg) of (Z)-endoxifen
• A group receiving 2 mg of (Z)-endoxifen

The study was double-blinded, meaning neither participants nor researchers knew who received which treatment until the trial concluded, ensuring unbiased results.

Measuring Breast Density and Safety

Mammographic breast density was assessed using full-field digital mammograms at the start, 3 months, 6 months, or upon early discontinuation. The STRATUS method, an automated system, measured breast density in square centimeters, with image alignment used to minimize errors.

Safety and tolerability were monitored through vital signs, blood chemistry, and participant-reported side effects via a digital app and questionnaires. The Breast Cancer Prevention Trial Eight Symptom Scale (BESS Plus), a validated symptom questionnaire, was used to evaluate tolerability, supplemented with questions specific to tamoxifen-related symptoms.

Results: Endoxifen Reduces Density with Fewer Side Effects

Of the over 126,000 women invited to participate, 240 were enrolled and randomly assigned. The trial’s primary goal was to determine whether either dose of (Z)-endoxifen was more effective than placebo in reducing mammographic breast density, a proxy for breast cancer risk reduction.

Statistical analysis focused on relative changes in breast density, adjusted for baseline values, and compared results between placebo and active treatment groups. The findings suggest that (Z)-endoxifen significantly reduced breast density with fewer side effects than tamoxifen, offering a potential new option for breast cancer prevention.

"If these results are confirmed in larger studies, (Z)-endoxifen could become a safer and more tolerable alternative to tamoxifen for breast cancer prevention." — Study Authors